Antinociceptive and Immune Effects of Delta-9-tetrahydrocannabinol or Cannabidiol in Male Versus Female Rats with Persistent Inflammatory Pain.

Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine if the two primary phytocannabinoids, THC and CBD, are effective treatments for persistent inflammatory pain. In Experiment 1, inflammation was induced in male and female rats by intraplantar injection of complete Freund's adjuvant (CFA). Then THC (0.0-4.0 mg/kg i.p.) or CBD (0.0-10 mg/kg i.p.) was administered twice-daily for 3 days. On day 4, vehicle, THC, or CBD was administered and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5-4 h post-injection. In Experiment 2, CFA- or mineral oil (control)-treated rats were given vehicle, THC (2.0 mg/kg), or CBD (10 mg/kg) in the same manner as in Experiment 1. Four h post-injection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC's effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little-to-no change in serum cytokines, whereas CBD decreased IL-1β, IL-10, and IFN-γ, and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but adjuvant-induced immune activation was greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain, in that THC maintains its efficacy with short-term treatment in both sexes, and does not induce immune activation. SIGNIFICANCE STATEMENT: CBDs and THCs pain-relieving effects are examined in male and female rats with persistent inflammatory pain to determine if individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provided preliminary insight into immune-related effects of cannabinoid-based therapy for pain.